Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Am J Respir Crit Care Med. 2013 May 15;187(10):1127-34. doi: 10.1164/rccm.201207-1210OC.
The dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose.
Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic parameters and pharmacokinetic/pharmacodynamic indices.
A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. The maximum tolerated dosage, pharmacokinetic parameters, and pharmacokinetic/pharmacodynamic index were determined. Therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed.
Maximum tolerated dosage of rifampin in the murine TB was 160 mg/kg/d. Pharmacokinetic measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a C(max) of 16.2 and 157.3 mg/L, an AUC(0-24h) of 132 and 1,782 h·mg/L, and AUC(0-24h)/minimum inhibitory concentration ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-week single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection.
Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/d enabled a significant reduction in therapy duration without adverse effects.
目前在结核病（TB）治疗中使用的 10mg/kg/d 利福平剂量不是最佳剂量。增加利福平剂量可能会缩短治疗时间。
确定在小鼠中使用最大治疗效果且无不良反应的最佳利福平剂量。评估相关药代动力学参数和药代动力学/药效学指数。
通过气管内细菌滴注，然后适当吸入，使小鼠处于垂直位置，建立使用北京基因型结核分枝杆菌菌株的小鼠 TB 感染模型。我们评估了 3 周内单药治疗中利福平的剂量依赖性活性。确定最大耐受剂量、药代动力学参数和药代动力学/药效学指数。评估了一系列利福平（R）剂量添加到异烟肼（H）和吡嗪酰胺（Z）方案中的治疗效果。
在小鼠 TB 中，利福平的最大耐受剂量为 160mg/kg/d。在 HR(10)Z 和 HR(160)Z 治疗方案中，利福平的药代动力学测量显示 Cmax 分别为 16.2 和 157.3mg/L，AUC(0-24h)分别为 132 和 1782h·mg/L，AUC(0-24h)/最低抑菌浓度比值分别为 528 和 7129。在 3 周的单药治疗后，利福平观察到明显的剂量效应相关性。HR(80)Z 的给药允许 9 周的治疗时间而不会复发感染。
我们的研究结果表明，目前在结核病治疗中使用的利福平剂量过低。在我们的小鼠 TB 模型中，80mg/kg/d 的利福平剂量可显著缩短治疗时间而无不良反应。
